Nitrazepam Tablets Bp 5mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nitrazepam Tablets BP 5mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5mg Nitrazepam PhEur.
3 PHARMACEUTICAL FORM
White uncoated tablets.
White, circular, flat bevelled-edge uncoated tablets impressed “C” and the identifying letters “NA” on either side of a central division line on one face.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1) Indicated for the short-term treatment of insomnia only when it is severe, disabling, or subjecting the individual to extreme stress and where daytime sedation is acceptable.
4.2 Posology and method of administration
Posology
The lowest effective dose should be employed, and treatment should, if possible, be intermittent. Dosage regimes should not extend beyond 4 weeks and treatment should gradually be withdrawn. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.
Adults: 5mg before retiring. This dose may be increased, if necessary, up to 10mg.
Elderly and debilitated patients: 2.5-5mg before retiring.
Children: Not recommended for children under 12 years of age.
Method of Administration For oral administration.
4.3 Contraindications
• Known hypersensitivity to benzodiazepines and any other ingredients in the
tablets
• Phobic or obsessional states; chronic psychosis
• Acute pulmonary insufficiency; respiratory depression (ventilatory failure may be exacerbated)
• Myasthenia gravis (condition may be exacerbated)
• Sleep apnoea (condition may be exacerbated)
• Severe hepatic insufficiency (elimination half-life of nitrazepam may be prolonged)
• Acute porphyria
4.4 Special Warnings and Precautions for Use
An underlying cause should be sought before deciding upon the use of benzodiazepines for symptomatic relief.
• Tolerance - Tolerance to their effects develops within 3-14 days of continuous use and hence treatment regimes should be kept to a minimum and repeat prescriptions avoided. Limits of tolerance in patients with organic cerebral changes (particularly resulting from arteriosclerosis) or cardiorespiratory insufficiency may be very wide; care must be taken in adapting the dosage with such patients.
• Dependence and Withdrawal - Withdrawal symptoms occur with benzodiazepines following normal therapeutic doses given for short periods of time.
Use of nitrazepam may lead to the development of physical and psychological dependence. The risk of dependence increases with the dose and duration of treatment, and in patients with a history of alcoholism and drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (see Section 4.8 Undesirable Effects).
• Rebound insomnia: a transient syndrome whereby the symptoms that led to treatment with nitrazepam may recur in an enhanced form on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
• Duration of Treatment - The duration of treatment should be as short as possible depending on the indication, but should not exceed 4 weeks including tapering off process. Treatment should not continue beyond 4 weeks without re-evaluation of the patient’s condition. Where long-term therapy is essential, it is recommended that the patient's requirements be reviewed on a regular basis.
It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively
decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while nitrazepam is being discontinued. Care is needed when switching from long acting benzodiazepines, such as nitrazepam, to a benzodiazepine with a short duration of action due to the risk of withdrawal symptoms developing.
• Amnesia: nitrazepam may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours. (See section 4.8)
• In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
• Care should be taken in patients with chronic renal or hepatic disease (elimination half-life of nitrazepam may be prolonged).
• Hypoalbuminaemia (may predispose patient to higher incidence of sedative side effects).
• Care should be exercised in prescribing nitrazepam for patients with a history of alcoholism or drug abuse as these patients are predisposed to habituation and dependence. Regular monitoring in such patients is essential. Alcohol should be avoided during treatment with nitrazepam (additive CNS depression).
• Depression or anxiety associated with depression. Benzodiazepines should not be used alone in the treatment of depression or anxiety associated with depression as suicide may be precipitated in such patients.
• Extreme caution should be used in prescribing nitrazepam to patients with personality disorders.
• Care should be excercised in patients with epilepsy since there have been reports of rare paradoxical exacerbation of seizures in these patients (See section 4.5).
• Psychiatric and paradoxical reactions: Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. They may be quite severe and are more likely in children and the elderly. Should they occur, use of the medicinal product should be discontinued.
• Specific patient groups: Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. Elderly should be given a reduced dose (see section 4.2).
• Benzodiazepines are not recommended for the primary treatment of psychotic illness.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
The following drug interactions with nitrazepam should be considered:
Enhancement of other CNS depressant drugs such as antipsychotics, narcotic analgesics (enhancement of euphoria may also occur, leading to an increase in psychological dependence), antidepressants, hypnotics, anaesthetics, sedative antihistamines, lofexidine, nabilone.
Alcohol (concomitant intake with alcohol is not recommended. The sedative effects may be enhanced when nitrazepam is used in combination with alcohol. This affects the ability to drive or use machines.)
Antiepileptic drugs (plasma phenytoin concentrations increased or decreased by nitrazepam. Side effects may be more evident with hydantoins or barbiturates). Dopaminergics (concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa).
Caffeine and theophylline (concurrent use may result in reduced sedative and anxiolytic effects of nitrazepam).
Cimetidine, oestrogen-containing contraceptives, disulfiram (these medicines may inhibit hepatic metabolism of nitrazepam).
Antibacterials (Rifampicin may increase the metabolism of nitrazepam. Isoniazid may inhibit the metabolism of benzodiazepines).
Antivirals (Ritonavir may inhibit benzodiazepine hepatic metabolism).
Antihypertensives (enhanced hypotensive effects. Enhances sedative effect with alpha blockers or moxonidine)
Baclofen and tizanidine (enhanced sedative effect).
Probenecid (may increase effects and possibility of excessive sedation).
4.6 Pregnancy and Lactation
An increased risk of congenital malformations in humans has been associated with its use, particularly in the first and second trimesters. If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding stopping if she intends to become or suspects she may be pregnant.
If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.
If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.
Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.
Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.
4.7 Effects on Ability to Drive and Use Machines
Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions).
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
- The medicine is likely to affect your ability to drive
- Do not drive until you know how the medicine affects you
- It is an offence to drive while under the influence of this medicine
- However, you would not be committing an offence (called ‘statutory defence’) if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely
4.8 Undesirable Effects
The following undesirable effects have been divided into the following categories: Very common: >1/10, Common: >1/100 to <1/10, Uncommon: >1/1,000 to<1/100 Rare: >1/10,000 to <1/1,000, Very rare: <1/10,000, not known (cannot be estimated from the available data)
|
Blood and the lymphatic system disorders Rare |
Blood dyscrasias |
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Immune system disorders Very rare |
Hypersensitivity reactions (anaphylaxia and angiooedema) |
|
Psychiatric disorders Uncommon |
Confusion, sleeping disorders, including insomnia. |
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Rare |
Psychiatric and paradoxical reactions (4). Muscular cramps, libido fluctuations |
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Not known |
Dependence and abuse of benzodiazepines, amnesia (2), depression (3), withdrawal symptoms (1) |
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Nervous system disorders Common |
Dizziness, sedation, unsteadiness, ataxia, drowsiness |
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Uncommon |
Disturbances in attention, tremor |
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Rare |
Dystonia, headache |
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Not known |
Dysarthria |
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Eye disorders Rare |
Visual disturbances |
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Not known |
Double vision |
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Ear and labyrinth disorders Rare |
Vertigo |
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Vascular disorders Rare |
Hypotension |
|
Respiratory, thoracic and mediastinal disorders Rare |
Respiratory depression |
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Gastrointestinal disorders Rare |
Nausea, gastrointestinal upsets |
|
Hepato-biliary disorders Rare |
Jaundice |
|
Skin and subcutaneous tissue disorders Rare |
Rash and other allergic skin reactions in the form of urticaria, pruritus, dermatitis, erythema multiforme, Stevens-Johnson syndrome |
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Renal and urinary disorders Rare |
Urinary retention |
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Musculoskeletal, connective tissue and bone disorders Uncommon |
Muscular weakness |
(1) Withdrawal effects on abrupt cessation of treatment - Depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea have been reported following abrupt cessation of treatment. In rare cases, withdrawal following excessive dosages may produce confusional states, psychotic manifestations and convulsions.
As with all benzodiazepines, withdrawal may be associated with physiological and psychological symptoms including depression.
(2) Anterograde amnesia may occur during the use of therapeutic doses since the risk is increased at higher doses. Amnesia may be combined with behavioural problems (see point 4.4).
(3) Existing depression may be revealed during the use of benzodiazepins (see also point 4.4).
(4) Reactions such as restlessness, excitation, irritability, aggressiveness, delusions, rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural side effects may occur during benzodiazepine treatment. They can be very serious with this product. These side effects are observed more frequently in children and elderly patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard
4.9 Overdose
As with other benzodiazepines overdose would not be life-threatening unless it is combined with other CNS-depressants (incl. alcohol).
When treating overdosage with any drug it should be borne in mind that several substances may be taken.
Symptoms:
Overdose with benzodiazepines is normally seen accompanied by different degrees of depression of the central nervous system, which may vary from lethargy to coma. In mild cases the symptoms include lethargy, mental confusion and drowsiness, and in more serious cases the symptoms include ataxia, hypotonia, hypotension, bradycardia, breathing difficulties, in rare cases coma and in very rare cases death.
Management:
Consider activated charcoal in adults or children who have taken more than 1mg/kg within 1 hour, provided they are not too drowsy. Gastric lavage is unnecessary if these drugs have been taken alone. Patients who are asymptomatic at four hours are unlikely to develop symptoms. Institute supportive measures as indicated by the patient's clinical state.
If CNS depression is severe consider the use of flumazenil a benzodiazepine antagonist. This should rarely be required. It has a short half-life (about an hour) and should not be used in mixed overdose or as a “diagnostic” test. Flumazenil is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Nitrazepam is a benzodiazepine sedative and hypnotic.
5.2 Pharmacokinetic properties
Nitrazepam is fairly readily absorbed from the GI tract, although there is some individual variation. It is extensively bound to plasma proteins. It is metabolised in the liver, mainly by nitroreduction and acetylation (which is reported to be subject to genetic polymorphism). It is excreted in the urine in the form of metabolites with only small amounts of a dose appearing unchanged. Up to about 20% of an oral dose is found in the faeces. It crosses the placental barrier and traces are found in breast milk.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6.1 List of excipients
Also contains lactose, magnesium stearate, maize starch, stearic acid.
6.2 Incompatibilities
None known
6.3 Shelf life
Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4 Special precautions for storage
Store below 25°C in a dry place.
Protect from light.
6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5-7g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.
Pack sizes: 28’s, 30’s, 56’s, 60’s, 84’s, 90’s, 100's, 112’s, 168’s, 180’s, 250's, 500's, 1000's.
Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.
Maximum size of bulk packs: 25,000.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER(S)
PL 0142/0086
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29 September 1977 21 April 1998
10 DATE OF REVISION OF THE TEXT
08/06/2015